SK286139B6 - Device for delivering metered aerosol formulations - Google Patents

Abstract

The device for delivering metered aerosol formulations, wherein the delivered aerosol formulations comprise an active ingredient in solution in a propellant consisting of hydrofluoroalkane (HFA) selected from 1,1,1,2-tetrafluoro-ethene (HFA 134a), 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) or mixture thereof, a co-solvent such as ethanol and optionally a low-volatility component preferably selected from glycerol, propylene glycerol, polyethylene glycol, oleic acid and isopropyl myristate, said device comprising a flat body (1) with a seat for housing the can (2), an inhalation mouthpiece (3) and an expansion chamber (4) shaped to create a vortex flow of the aerosol particles expelled by an actuator orifice (5), and the actuator orifice diameter is in the range between 0.30 and 0.50 mm.

Description

Technical field

The invention relates to an aerosol inhaler.

BACKGROUND OF THE INVENTION

Pressurized metered dose inhalers are well known devices for administering pharmaceutical products to the respiratory tract by inhalation.

Active materials that are generally administered by inhalation include bronchodilators such as β2 agonists and anticholinergics, corticosteroids, antileukotrienes, antiallergics and other drugs that can be effectively administered by inhalation, thereby increasing the therapeutic index and reducing their side effects.

Despite their apparent simplicity, conventional pressurized metered aerosol canisters are difficult to use properly, as is confirmed by many scientific literature claiming that most patients use them incorrectly, either because they are unable to synchronize the canister compression with inhalation and therefore do not inhale the drug. at the right time or because they do not maintain an adequate inhalation flow or, among other reasons, do not breathe deep enough.

This problem becomes even more important in certain patients, such as children, elderly patients and patients with reduced respiratory or manual capabilities.

Even if the aerosol drug delivery container is used correctly, the availability of the inhaled medicament for the airways largely depends on the size of the aerosol droplets, which in turn depends on the formulation and the time of evaporation of the propellant.

It is well documented that even under the most favorable conditions, only 10% of the aerosol dose administered reaches the respiratory tract. A similar percentage is exhaled or deposited outside the oral cavity, while as a result of high velocity impact, about 80% is deposited in the oropharyngeal cavity, swallowed and absorbed systemically, and is therefore practically lost.

However, the amount of inhaled drug is usually sufficient to produce a pharmacological effect. However, if the vial is not used properly, the amount of drug that reaches the site of action at the lung level will further decrease and the therapeutic response will be compromised.

Over-deposition of the aerosol in the oropharyngeal cavity can also lead to adverse effects either at systemic level due to drug absorption or at the local level, as in the case of corticosteroids, which can lead to oral candidiasis. In order to overcome the problems associated with the use of canisters delivering metered doses of aerosol medicines, auxiliary delivery systems have been developed over the past decade to apply to the nozzles of the thankful canisters, which, depending on their shape and size, can be classified as "spacers" or "reservoirs".

Among the cartridges, the Volumatic (Glaxo-Wellcome) is one of the best known and most used, while the Aerochamber (3M) is one of the most used and best known among spacers or auxiliary devices of small size.

European patent EP-B-0475257 discloses a device for inhalation through the mouth with pressurized containers for delivering metered doses of medicament. This device is highly efficient and has a reduced size so it can be easily placed in a small handbag or even in a jacket pocket.

The device (shown in Fig. 1) consists mainly of a flat body with a receptacle space provided with an inhalation mouthpiece and an expansion chamber shaped to produce a swirling flow at which the aerosolized material is expelled through the feeder, in which the particles remain suspended for long enough to lose their kinetic energy and allow substantially vaporization of the propellant followed by particle size reduction, resulting in more efficient intra-pulmonary and intra-pulmonary delivery, while large particles are centrifuged onto the chamber walls to settle thereon.

Metered-dose inhalers use propellant to expel droplets containing the pharmaceutical product into the respiratory tract as an aerosol.

For many years, the preferred propellants used in pharmaceutical aerosols have been the group of chlorofluorocarbons commonly referred to as CFCs or CFCs, such as CC1 ₃ F (Freon 11 or CFC-11), CC1 ₂ F ₂ (Freon 12 or CFC-12) and CClF ₂ -CClF ₂ (Freon 114 or CFC-114).

The device described in EP-B-0475257, sold under the name Jet, has hitherto been used for the administration of aerosol medicaments in the form of chlorofluorocarbon suspensions.

At present, propellants from chlorofluorocarbons such as Freon 11 and Freon 12 are involved in the destruction of the ozone layer and their production is phased out.

Fluoroalkanes (HFAs), also known as fluorocarbons (HFCs), which do not contain any chlorine, are considered less destructive to ozone and have been proposed to replace CFCs.

HFA and especially 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoro-propane (HFA 227) are recognized as the best candidates for CFC-free propellants and more drug aerosol formulations using such HFA propellant systems have already been described in many patent applications.

In international application no. PCT / EP98 / 03533, filed 10/6/98, discloses solution compositions for use in an aerosol inhaler comprising an active material, a fluoroalkane (HFA) containing propellant, preferably 134a or 227, or mixtures thereof, a cosolvent, preferably ethanol and further comprising a low volatility component, preferably selected from glycerol, propylene glycol, polyethylene glycol, oleic acid and isopropyl myristate, to increase the mean mass aerodynamic diameter (MMAD) of the aerosol particles when actuating the inhaler.

As already mentioned, the efficacy of an aerosol device, for example a pressurized metered dose inhaler, is a function of the dose stored in the appropriate location in the lungs.

Deposition is influenced by several factors, one of the most important being the aerodynamic size of the particles that make up the aerosol.

The solid particles and / or droplets dispersed in the aerosol formulation can be characterized by their average mass aerodynamic diameter (MMAD), i. j. the diameter around which the mass of the particles is distributed equally.

The deposition of particles in the lungs largely depends on three physical mechanisms: 1. impact, particle inertia functions; 2. sedimentation due to gravity; and 3. diffusion resulting from Brownian motion of fine, submicrometer (<1 µm) particles.

The mass of the particles determines which of the three main mechanisms prevails.

The effective aerodynamic diameter is a function of the size, shape and density of the particles and affects the magnitude of the forces acting on them. For example, while the inertia and gravity effects increase with increasing particle size, the displacements caused by diffusion decrease. Therefore, the MMAD of aerosol particles is particularly important for deposition of particles in the respiratory tract. GSD (geometric standard deviation) is a measure of the variation in particle diameter in an aerosol.

Aerosol particles of equivalent aerodynamic size exhibit similar lung deposition regardless of their effective size and composition.

Particles with an aerodynamic diameter of about 0.8 to 5 µm are generally considered to be respirable.

Particles having a diameter greater than 5 µm are primarily deposited by impact inertia in the oropharynx, particles with a diameter of 0.5 to 5 µm, mainly affected by gravity, are ideal for storage in the respiratory tract, and particles with a diameter of 0.5 to 3 µm are desirable to deliver an aerosol to the peripheral lung.

Particles smaller than 0.5 µm may be exhaled.

Another parameter that characterizes the efficiency of a metered dose aerosol is the fine particle dose (FPD) delivered, which allows direct measurement of aerosol particles that fall within a specified size range.

The particle size analysis in the aerosol is measured according to European Pharmacopoeia Ed. III, 1997, using the Andersen Cascade Impactor, a device that captures aerosol particles in dependence on aerodynamic diameter, thereby performing particle size analysis.

Eight degrees with different boundaries can be used. The particle size distribution profile is obtained by plotting the weight of drug deposited at each step against the corresponding cutoff diameters.

Lewis, D. A. et al., In Respirators Drug Delivery VI, p. 363-364, 1998, that using commercially available controls for delivering HFA-pressurized aerosol solution formulations, reducing the orifice diameter would result in a fine particle dose (FPD) increase with a small but statistically insignificant reduction in mean mass aerodynamic diameter (MMAD).

The essence of you finding

It has now been found that when using the Jet actuator described in said EP-B-0475257 to deliver aerosol formulations in an HFA solution, the FPD is not affected by the diameter of the actuator bore in the range between 0.30 and 0.50 mm. Conversely, it has been observed that when conventional actuators are coupled to other commercial spacer or reservoirs such as Aerochamber or Volumatic, the FPD and MMAD values change compared to those obtained with a simple actuator, but the relationship between the diameter of the actuator aperture and The FPD does not change, and in this case too, the fine particle dose is increased when the diameter of the actuator bore is reduced.

The MMAD values of the formulations administered by the Jet device do not differ significantly from the doses administered with a standard controller.

Another problem with metered dose aerosol therapy is that as the number of administrations increases, the use of the article may reduce the diameter of the aperture due to deposit of thicker particles on it.

Partial blockage of the actuator bore when a standard actuator is connected to a container such as a Volumatic will increase both the delivered dose and the fine particle dose. Therefore, repeated actuations result in insufficient dose uniformity.

It has now been found that a Jet actuator, in contrast to conventional actuators associated with or without a reservoir or spacer, makes it possible to achieve a reproducible delivered dose as well as an FPD upon repeated actuation.

Accordingly, the present invention provides a device for delivering metered doses of aerosols containing an active ingredient in a solution in a propellant consisting of a fluoroalkane (HFA) selected from 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2 , 3,3,3-heptafluoropropane (HFA 227) or mixtures thereof, a cosolvent such as ethanol, and optionally a low volatility component, preferably selected from glycerol, propylene glycol, polyethylene glycol, oleic acid and isopropyl myristate, which comprises a flat body 1 with space for insertion of a container 2, an inhalation mouthpiece 3, and an expansion chamber 4 shaped to create a swirling flow of aerosol particles expelled by the actuator 5, wherein the diameter of the opening of the actuator 5 is between 0.30 and 0.50 mm.

The results are shown in the following examples.

Overview of the figures in the drawing

The figure shows a device for delivering metered doses of aerosols.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Containers 2 containing various HFA 134a solution formulations of beclomethasone dipropionate (BDP) in the presence of ethanol and optionally a low volatile component such as glycerol were equipped with:

- various types of standard actuators 5 with hole diameters ranging from 0.25 to 0.50 mm;

various types of Jet actuators 5 with bore diameters ranging from 0.30 to 0.50 mm;

- various types of standard actuators 5 with bore diameters ranging from 0.25 to 0.42 mm associated with Aerochamber and Volumatic.

The particle size distributions and MMAD of aerosol particles administered by various combinations were determined by tests performed with an Andersen Cascade Impactor. In such assays, FPD was calculated as the mass of particles deposited from stage 3 to the filter, and therefore with an aerodynamic diameter of less than 4.7 µm.

The results shown in Tables 1 to 6 are the mean of two to six administrations for each device.

Table 1

Fine Particle Dose (FPD) as a Function of Standard Controller Hole Diameter 5

Formulation: BDP

Ethanol mg / 10 ml (250 µg / dose)% ± 0.5 wt. to 12 ml

HFA 134a

Hole diameter of standard actuator (mm) 0.25 0.33 0.42 0.50 Dose administered (pg) 206 222 209 210 FPD (pg) 105 66 41 33 MMAD (pm) 1.4 1.8 1.7 1.8 GSD 1.9 2.2 2.3 2.6

The dose administered is the amount of drug delivered from the device obtained at all stages of the Andersen Cascade Impactor.

FPD is the fine particle dose, calculated as the weight of the particles deposited from stage 3 to the filter, and therefore with an aerodynamic diameter of less than 4.7 µm.

MMAD is the mean mass aerodynamic diameter, t. j. the diameter around which the mass of the particles is distributed equally.

GSD is the geometric standard deviation, a measure of the variation in particle diameter in an aerosol.

Table 2

Fine Particle Dose (FPD) as a function of hole diameter of standard actuator 5

Formulation: BDP Ethanol Glycerol HFA 134a mg / 10 ml (250 µg / dose)% ± 0.5 wt.

1.3 wt.

to 12 ml

Hole diameter of standard actuator (mm) 0.25 0.33 0.42 0.50 Dose administered (pg) 221 242 229 216 FPD (pg) 94 55 46 35 MMAD (pm) 2.6 2.6 3.0 2.9 GSD 2.0 2.3 2.3 2.3

Table 3

Fine Particle Dose (FPD) as a function of Jet Driver Hole Diameter 5

Formulation: BDP Ethanol Glycerol HFA 134a mg / 10 ml (250 µg / dose)% ± 0.5 wt.

1.3 wt.

to 12 ml

Drill Hole Diameter (mm) 0.30 0.35 0.40 0.45 Dose administered (pg) 76 76 80 77 FPD (pg) 58 57 53 55 MMAD (pm) 2.3 2.4 2.7 2.5 GSD 2.0 1.9 2.0 1.9

Table 4

Fine Particle Dose (FPD) as a function of Jet Driver Hole Diameter 5

Formulation: BDP 50 mg / 10 ml (250 µg / dose)

Ethanol 15% ± 0.5% wt.

HFA 134a to 12 ml

Drill Hole Diameter (mm) 0.30 0.35 0.40 0.45 0.50 Dose administered (pg) 77 81 79 72 74 FPD (pg) 67 71 62 59 59 MMAD (pm) 1.4 1.5 1.6 1.7 1.7 GSD 2.1 2.1 2.1 2.0 2.0

Table 5

Fine particle dose (FPD) as a function of hole diameter of standard actuator 5 associated with Aerochamber

Formulation: BDP Ethanol Glycerol HFA 134a mg / 10 ml (250 µg / dose) 15% ± 0.5% w / w.

1.3 wt.

to 12 ml

Hole diameter of standard actuator (mm) 0.25 0.30 0.42 Dose administered (pg) 114 96 74 FPD (pg) 82 68 45 MMAD (pm) 2.6 2.5 2.6 GSD 1.9 1.9 1.9

It can be seen that there is a significant increase in FPD with a reduction in hole diameter.

Table 6

Fine Particle Dose (FPD) as a function of hole diameter of standard actuator 5, coupled to Volumatic

Formulation: BDP Ethanol Glycerol HFA 134a mg / 10 ml (250 µg / dose)% ± 0.5 wt.

1.3 wt.

to 12 ml

Hole diameter of standard actuator (mm) 0.25 0.30 0.42 Dose administered (pg) 169 132 118 FPD (pg) 120 87 74 MMAD (pm) 3.1 3.3 3.5 GSD 1.6 1.6 1.8

Here again, the FPD increases significantly with the hole diameter decreasing.

Example 2

Metered dose vials 2 containing the same HFA 134a beclomethasone solution formulation (BDP) were equipped with:

- various types of standard actuators 5 with bore diameters ranging from 0.30 to 0.42 mm associated with Aerochamber and Volumatic;

- Drive control 5 with hole diameter 0.40 mm.

The administered dose and FPD were evaluated with increasing numbers of administrations. Dose and FPD values are the mean of ten administrations. The particle size distributions and MMAD of aerosol particles administered by various combinations were determined by tests performed with an Andersen Cascade Impactor.

The results shown in Table 7 confirm that repeated actuations result in a significant increase in FPD with a reduction in hole diameter.

In the case of Volumatic, an increase in both the administered dose and the fine particle dose is also evident upon repeated actuations.

Table 7

Comparison of the effect of Jet, Aerochamber and Volumatic actuators 5 on the delivered dose and the fine particle dose (FPD) after repeated actuations

Formulation: BDP Ethanol Glycerol HFA 134a mg / 10 ml (250 µg / dose)% ± 0.5 wt.

1.3 wt. to 12 ml

driver Vessel and actuator diameters (mm) Number of submissions Dose administered (pg) FPD (pg) MMAD (pm) GSD go B (0.40) 21 -30 93 65 2.8 1.9 B (0.40) 141 - 150 85 51 3.0 1.9 C (0.40) 55 -65 95 58 3.0 1.9 C (0.40) 161 -170 96 57 3.0 1.9 aero- B (0.30) 36 -45 n. a. 68 2.5 1.9 chamber C (0.30) 146 - 155 86 68 2.8 1.8 B (0.42) 111 - 120 56 45 2.6 1.9 C (0.42) 86 -95 59 47 2.7 1.9 Voluma- B (0.30) 81 -90 118 87 3.3 1.6 the C (0.30) 131 - 140 88 67 3.1 1.7 B (0.42) 126 - 135 108 74 3.5 1.6 C (0.42) 71 -80 74 56 3.2 1.6

n. a. not available

Claims (1)

PATENT CLAIMS Apparatus for delivering metered doses of aerosols comprising an active ingredient in solution in a propellant consisting of a fluoroalkane (HFA) selected from 1,1,1,2-tetrafluoroethane (HFA 134a) and 5 1,1,1,2, 3,3,3-heptafluoropropane (HFA 227) or mixtures thereof, a cosolvent such as ethanol, and optionally a low volatility component, preferably selected from glycerol, propylene glycol, polyethylene glycol, oleic acid and isopropyl myristate, characterized in that it comprises a flat body ( 1) with a receptacle space (2), an inhalation mouthpiece (3) and an expansion chamber (4) for generating a swirling flow of aerosol particles expelled by the actuator (5), wherein the diameter of the actuator bore (5) is in the range between 0.30 and 0.50 mm.